Moderation of breastfeeding effects on the IQ by genetic variation in fatty acid metabolism.

Medical Research Council Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London SE5 8AF, England. a.caspi@iop.kcl.ac.uk

Abstract

Children's intellectual development is influenced by both genetic inheritance and environmental experiences. Breastfeeding is one of the earliest such postnatal experiences. Breastfed children attain higher IQ scores than children not fed breast milk, presumably because of the fatty acids uniquely available in breast milk. Here we show that the association between breastfeeding and IQ is moderated by a genetic variant in FADS2, a gene involved in the genetic control of fatty acid pathways. We confirmed this gene-environment interaction in two birth cohorts, and we ruled out alternative explanations of the finding involving gene-exposure correlation, intrauterine growth, social class, and maternal cognitive ability, as well as maternal genotype effects on breastfeeding and breast milk. The finding shows that environmental exposures can be used to uncover novel candidate genes in complex phenotypes. It also shows that genes may work via the environment to shape the IQ, helping to close the nature versus nurture debate.

The association between breastfeeding and IQ is moderated by a genetic polymorphism (rs174575) in the FADS2 gene. In each cohort, we estimated a hierarchical regression model (ordinary least squares) with main effects for genotype (C carriers vs. GG homozygotes) and environment (not breastfed vs. breastfed) followed by a multiplicative genotype × environment interaction term, with covariate adjustment for socioeconomic status. In the Dunedin cohort (A), the effect of breastfeeding was significant (t = 4.67, P < 0.001), the effect of rs174575 was not significant (t = 0.32, P = 0.75), and the interaction term was significant (t = 2.11, P = 0.035). In the E-risk cohort (B), the effect of breastfeeding was significant (t = 3.20, P < 0.001), the effect of rs174575 was not significant (t = 1.82, P = 0.42), and the interaction term was significant (t = 2.37, P = 0.018).

The FADS1 and FADS2 gene structure on chromosome 11q12.2. The FADS1 and FAD2 genes are arranged in a head-to-head orientation. The figure shows the position of rs174575 in relation to the hypothetical promoter regions (green rectangles), hypothetical transcription factor binding site SRE (blue arrowheads) (), and 18 SNPs that have been related to individual differences in fatty acid composition among humans (). Of these 18 SNPs, 9 (shown in red) are validated in publicly available data via HapMap. r2 between rs174575 and each of the nine markers found in HapMAP CEU () is noted in parentheses. Further suggesting common regulatory mechanisms for these two genes, publicly available gene expression data on lymphoblastoid cell lines from 57 unrelated CEPH individuals (GEO accession no. GDS2106) show that FADS1 gene expression correlates 0.78 with FADS2 gene expression. Similarly, in mouse BXD strains, FADS1 and FADS2 gene expression correlate 0.61 ().